Crystalline pharmaceutical product

ABSTRACT

This invention provides (S)-7-[(4,4&#39;-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, hydrochloride, processes for its preparation and methods for its use.

This application claims benefit of provisional application Ser. No.60/025,369 filed Sep. 3, 1996. This application is a 371 ofPCT/US97/15292 filed Aug. 29, 1997.

FIELD OF THE INVENTION

This invention relates to a crystalline salt form of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, its preparation and use as atherapeutic substance.

BACKGROUND

The compound(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, given by formula (I), and procedures

for preparing such compound, its trifluoroacetic acid and sodium saltsare disclosed in WO 95/18619 (PCT/U.S. Ser. No. 95/00248, SmithKlineBeecham Corp.). Since this compound has both a basic and acidic center,it may exist as either an acid addition salt or basic addition salt. Ifneither an acid nor a basic addition salt is formed, it may exist as aninternal salt or zwitterion. This compound is an inhibitor of theGPIIbIIIa (fibrinogen) receptor on platelets and it acts to inhibitplatelet aggregation. Thus, the compound is useful for treating suchailments as stroke, myocardial infarction, thrombosis, embolism, andrestenosis following angioplasty. The zwitterion and trifluoroacetatesalt prepared according to WO 95/18619 possess undesirablecharacteristics for preparing pharmaceutical formulations of thiscompound for commercial sale. The zwitterion is hygroscopic and tends tohave a variable water content, equilibrating toward a species whichtakes up about six molar equivalents of water. This may cause difficultyin milling and mixing to create pharmaceutical compositions. Thetrifluoroacetate salt is not thermally stable for an extended periodwhich impairs its shelf life.

Accordingly, a stable form of the compound which possesses desirablephysical characteristics is needed.

SUMMARY OF THE INVENTION

This invention comprises a stable hydrochloride salt of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid.

In another aspect, this invention comprises a stable pharmaceuticalcomposition of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride.

In yet another aspect, this invention comprises a method of antagonizingthe fibrinogen receptor for preventing or treating diseases whereinplatelet aggregation or the binding of ligand to the fibrinogen receptoris a factor.

DETAILED DESCRIPTION

It has now been found that(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid may be prepared as a hydrochloride salt which is crystalline,stable and possesses a consistent water content. Its preparation andphysical properties appear to be consistent and reproducible, which makeit particularly useful for use in a commercial product.

The present invention provides (S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride, formula (I), as a novel material, and, inparticular, as a pharmaceutically acceptable form. The materialcrystallizes preferably with one mole of HCl, and appears to exist in agenerally anhydrous form. Although small amounts of water may bedetected by Karl Fischer analysis, this is generally less than 1-2% w/wof the drug substance, and it appears to be consistent irrespective ofthe storage conditions. The hydrochloride does not appear to exist inpolymorphic forms, but in a single microcrystalline aggregate formranging from 10 to 250 microns. Accordingly, the hydrochloride salt formoffers significant advantages for bulk material consistency, handling,and formulation. In addition, the hydrochloride salt form exhibitsenhanced dissolution and solubility in water.

In a preferred aspect, this invention provides(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride in substantially pure form.

The present invention also provides a process for preparing(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride which comprises forming a solution of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride and crystallizing the hydrochloride salt fromsolution by precipitation or recrystallization. The solution may beprepared in any conventional manner, such as by dissolving the(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, or a suitable salt, in a suitable solvent, and adding hydrogenchloride as a gas, or dissolved in a second solvent to the solution. Thesecond solvent may be the same or different from that used in theoriginal solution. Preferably the second solvent will be miscible withthe solvent for the benzodiazepine. Water is a useful solvent. Alcohols,especially methanol, ethanol, and isopropanol, are particularlypreferred organic solvents for dissolving the hydrochloric acid andmaking the hydrochloride salt.

The hydrochloride salt may be precipitated from the solution by adding asolvent in which the salt if less soluble than the solvent in which thesalt is prepared or by inducing crystallization, for instance bychilling the solution, adding a co-solvent, adding a seed crystal, ormerely allowing the solution to stand. Alternatively, the hydrochloridesalt may be precipitated by concentrating the solution of thehydrochloride salt, e.g., removing the solvent(s), such as byevaporation. In another alternative, the solvent may be removed, and theresidue may be treated with another solvent, or mixture of solvents, toinduce crystallization.

Although the process is preferably carried out starting with a solutionof the zwitterionic form of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, the hydrochloride may be prepared using other salts, for instancean acid addition salt, such as the acetate or trifluoroacetate salt, ora basic addition salt, such as an alkali metal (e.g., lithium, sodium orpotassium) or organic amine salt.

In one embodiment, the(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid is suspended in water, and titrated with an aqueous solution ofhydrochloric acid to a pH of about 2-3. During the addition of acid, thesolid dissolves to give a clear solution. It is important to avoid anexcess of the acid, about one equivalent is desired, to produce a stableand readily crystallizable salt. Evaporation of the water yields a crudehydrochloride salt which may be recrystallized from an appropriatesolvent, such as ethanol to yield a purified hydrochloride salt.

(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid as a zwitterion may be prepared according to the procedures setforth in WO 95/18619 and WO 97/24336 (PCT/IB96/01502, SmithKlineBeecham) which are incorporated herein by reference as though fully setforth.

This invention further provides a pharmaceutical composition whichcomprises(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride and a pharmaceutically acceptable carrier.Accordingly, (S)-7-[(4,4′-bipiperidin- 1-yl)carbonyl]-2,3,4,5-tetrahydro4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride may be used in the manufacture of a medicament.Pharmaceutical compositions may be formulated as a solution or powderfor parenteral administration. Powders may be reconstituted by additionof a suitable diluent or other pharmaceutically acceptable carrier priorto use. The liquid formulation may be a buffered, isotonic, aqueoussolution. Examples of suitable diluents are normal pyrogen-free water,isotonic saline solution, standard 5% dextrose in water or bufferedsodium or ammonium acetate solution. Such formulation is especiallysuitable for parenteral administration, but may also be used for oraladministration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be desirable to add excipients such aspolyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethyleneglycol, mannitol, sodium chloride or sodium citrate.

Preferably, the(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride may be encapsulated, tableted or prepared in aemulsion or syrup for oral administration. Pharmaceutically acceptablesolid or liquid carriers may be added to enhance or stabilize thecomposition, or to facilitate preparation of the composition. Solidcarriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. Liquid carriers include syrup, peanut oil, olive oil, salineand water. The carrier may also include a sustained release materialsuch as glyceryl monostearate or glyceryl distearate, alone or with awax. The amount of solid carrier varies, but, preferably, will bebetween about 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulating, and compressing, when necessary,for tablet forms; or milling, mixing and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule. Capsules and tablets arepreferred dosage forms.

For rectal administration, the compound may also be combined withexcipients such as cocoa butter, glycerin, gelatin or polyethyleneglycols and molded into a suppository.

This invention also provides a method of inhibiting platelet aggregationand clot formation in a mammal, especially a human, which comprises theinternal administration of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride and a pharmaceutically acceptable carrier.Indications for such therapy include acute myocardial infarction (AMI),deep vein thrombosis, pulmonary embolism, dissecting aneurysm, transientischemia attack (TIA), stroke and other infarct-related disorders, andunstable angina. The compounds of this invention are also useful forpreventing restenosis of an artery or vein in a mammal followingangioplasty. Chronic or acute states of hyper-aggregability, such asdisseminated intravascular coagulation (DIC), septicemia, surgical orinfectious shock, post-operative and post-partum trauma, cardiopulmonarybypass surgery, incompatible blood transfusion, abruptio placenta,thrombotic thrombocytopenic purpura (TTP), snake venom and immunediseases, are likely to be responsive to such treatment. These compoundsare also believed to be useful for adjunct therapy followingangioplasty.

The compound of this invention may also be favorably administered withother agents which inhibit platelet aggregation. For instance, the(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride may be administered with compounds of the class ofcyclooxygenase inhibitors, thromboxane antagonists, thromboxanesynthetase inhibitors, heparins, thrombin inhibitors, ADP receptorinhibitors/antagonists and ticlopidine. Examples of such agents areaspirin, warfarin and clopidogrel.

The pharmaceutical composition is administered either orally orparenterally to the patient, in a manner such that the concentration of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride in the plasma is sufficient to inhibit plateletaggregation, or other such indication. The pharmaceutical compositioncontaining the drug is administered at a dose between about 0.2 to about50 mg/kg of active compound in a manner consistent with the condition ofthe patient. For acute therapy, parenteral administration is preferred.For persistent states of hyperaggregability, an intravenous infusion ofthe compound in 5% dextrose in water or normal saline is most effective,although an intramuscular bolus injection may be sufficient.

For chronic, but noncritical, states of platelet aggregability, oraladministration of a capsule or tablet, or a bolus intramuscularinjection is suitable. The compound is administered one to four timesdaily at a level of about 0.4 to about 50 mg/kg to achieve a total dailydose of about 0.4 to about 200 mg/kg/day. Preferably, it is administeredabout two times daily at a level of about 50 to 600 mg/dose.

This invention further provides a method for inhibiting the reocclusionor restenosis of an artery or vein following fibrinolytic therapy, whichcomprises internal administration of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride and a fibrinolytic agent. Administration of thecompound in fibrinolytic therapy either prevents reocclusion completelyor prolongs the time to reocclusion.

Methods for assessing the ability of the compound of this invention toinhibit the fibrinogen receptor and inhibit platelet aggregation arecommon in the art and may be found for instance in WO 95/18619 (PCT/U.S.Ser. No. 95/00248, SmithKline Beecham Corp.) and WO 94/14776 (PCT/U.S.Ser. No. 93/12436, SmithKline Beecham Corp.).

The examples which follow are intended to in no way limit the scope ofthis invention, but are provided to illustrate how to make and use thecompounds of this invention. Many other embodiments will be readilyapparent and available to those skilled in the art.

EXAMPLES

In the Examples, all temperatures are in degrees Centigrade. Massspectra were performed using fast atom bombardment (FAB) orelectro-spray (ES) ionization. Melting points were taken on aThomas-Hoover capillary melting point apparatus and are uncorrected.Optical rotations were determined on a Perkin Elmer 241 polarimeter,using a 10 cm path length cell. The melting point and optical rotationof samples may vary upon repeated experiments, but they are reproduciblewithin about 5%.

NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer, unlessotherwise indicated. Chemical shifts are reported in ppm (5) downfieldfrom tetramethylsilane. Multiplicities for NMR spectra are indicated as:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet ofdoublets, dt=doublet of triplets etc. and br indicates a broad signal. Jindicates the NMR coupling constant in Hertz.

EXAMPLE 1

Preparation of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride

(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, 1.5 hydrate (4.0 g, 9.3 mmol) was suspended in water (20 mL) andstirred. Concentrated (12 N) hydrochloric acid was added dropwise whilemonitoring the pH of the mixture. The solid material dissolved as theacid was added to yield a yellowish solution, and the pH was lowered to2.4. The water was evaporated under reduced pressure to yield aglass.(5.0 g). This material was stirred and triturated with absoluteethanol (10 mL) to yield a crystalline solid. The solid was filtered andair-dried to yield the title compound. Mp(ethanol) 292.5-293.5° C.[α]D25° (c 0.5, MeOH) −176.2. Anal. (C₂₃H₃₂N₄O₄.HCl) calcd: C, 59.41; H,7.15; N, 12.05. found: C, 59.11; H, 7.22; N, 11.67.

Comparison between(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid (zwitterion) and(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride (HCl Salt).

Property Zwitterion HCl Salt Thermal Stability some degradation, Stable,no increase in (solid samples, 3 days increase in organic organicimpurities at 100° C.) impurities by 1.3% (hplc, by area) Polarizedlight prismatic needle type microcrystalline microscopy crystals(100-500 (10-250 microns) microns) Hygroscopicity (% t = 0  5.6 t = 00.9 w/w Karl Fischer t = 21 days 20.1 t = 21 days 0.8 analysis)

The hydrochloride salt has also been found to be about ten times moresoluble in water than the zwitterion.

EXAMPLE 2

Pharmaceutical Composition

For preparing a standard 200 mg capsule containing 20 mg of the activedrug product, the following components are used:(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride (21.7 mg), microcrystalline cellulose N.F. (57.7mg), magnesium stearate N.F. (2 mg), pregelatinized starch N.F. (q.s. ad200 mg). All ingredients are screened with a #40 mesh stainless steelscreen. A suitable mixer/blender, such as a Paterson Kelly V blender, ischarged with an equal portion of the pregelatinized starch,microcrystalline cellulose and the hydrochloride salt, and mixed well.Portions of pregelatinized starch and microcrystalline cellulose areadded in geometric increments and mixed. Finally the magnesium stearateis added and blended to produce the final capsule mix which is thenfilled into a size 2 hard gelatin capsule.

What is claimed is: 1.(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride.
 2. The compound of claim 1 having a melting pointof about 291° C.
 3. The compound of claim 1 having a negative specificrotation of about
 175. 4. A pharmaceutical composition comprising thecompound of claim 1 and a pharmaceutically acceptable carrier.
 5. Aprocess for preparing the compound of claim 1 which comprises forming asolution of(S)-7-[(4,4′-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid, hydrochloride and crystallizing said hydrochloride salt byprecipitation or recrystallization.
 6. A method of inhibiting plateletaggregration which comprises administering the compound of claim 1 to amammal in need thereof.
 7. A method of treating myocardial infarction,thrombosis, embolism, stroke and infarct-related disorders, orrestenosis following angioplasty, which comprises administering thecompound of claim
 1. 8. A method for inhibiting the reocclusion orrestenosis of an artery or vein following fibrinolytic therapy, whichcomprises internal administration of a compound according to claim 1 anda fibrinolytic agent.
 9. A method for inhibiting platelet aggregationcomprising administering a compound according to claim 1, and acyclooxygenase inhibitor, a thromobxane synthesis inhibitor, athromboxane antagonist, a heparin, a thrombin inhibitor, an ADPinhibitor.
 10. A method for inhibiting platelet aggregation comprisingadministering a compound according to claim 1 and aspirin, ticlopidine,warfarin or clopidogrel.
 11. A method according to claim 6 for treatingor preventing myocardial infarction.
 12. A method according to claim 6for treating or preventing unstable angina.
 13. A method according toclaim 6 for treating or preventing transient ischemia attack.
 14. Amethod according to claim 6 for treating or preventing stroke.
 15. Amethod according to claim 6 for preventing restenosis of an artery orvein following angioplasty.
 16. A method for inhibiting plateletaggregation comprising administering a compound according to claim 1 andaspirin.
 17. A pharmaceutical composition according to claim 4comprising a 20 mg unit dose.